Simvastatin Synthase

Introduction
Simvastatin synthase (LovD) is a 46 kDa acyltransferase found in the lovastatin biosynthetic pathway and catalyzes the final step of lovastatin biosynthesis. Pictured here is the generated double mutant C40A/C60N (G0), from wild type LovD (Figure 1).

This enzyme is isolated from the natural product biosynthetic pathways of Aspergillus terreus, specifically the polyketide biosynthetic pathway. Simvastatin Synthase converts the inactive monacolin J acid (MJA) by dimethylbutyryl chloride to yield the protected form of simvastatin (Figure 2), which subsequently undergoes lactonization to yield simvastatin.



LovD can also synthesize the blockbuster drug simvastatin using MJA and a synthetic α-dimethylbutyryl thioester.

Exploring the structure
LovD is a 413-amino acid protein predicted to have an α/β hydrolase fold based on primary sequence analysis. LovD has of two domains. The first domain, which consists of residues 1–92 and 204–413, is a central seven-stranded antiparallel β-sheet flanked by α-helices on either face. The second domain is smaller, consists of residues 93–203 and is primarily α-helical.

At the core of the enzyme, there are notable loops peripheral to the active site, both in size and architecture. Upon ligand binding LovD undergoes a conformational change analogous to the closing of a catcher's mitt by these loops. This ringshaped ridge over the active site with fingers is composed of five loops : residues 114–125, 147–173, 243–258, 321–327, and 388–391.

LovD has nine cysteines at the following positions: C40, C49, C60, C72, C89, C216, C266, C380, and C395.

Additional Information
 As simvastatin is an active pharmaceutical ingredient in the cholesterol-lowering drug Zocor®, its efficient synthesis from lovastatin, via LovD is intensely pursued.

The protein-protein interaction between LovD and the acyl carrier protein domain of LovF facilitates the highly efficient tailoring reaction during LVA biosynthesis. The α-S-methylbutyrate side chain is synthesized by the lovastatin diketide synthase (LDKS) LovF and then transferred by LovD regioselectively to the C8 hydroxyl of MJA.

Among enzymes that of known structures, EstB (cephalosporin esterase), is homologous to LovD: 26% sequence identity.